1. Field of the Invention
The present invention relates to methods and apparatus for enhancing nerve regeneration and growth, and more particularly relates to a method and apparatus for stimulating axon and dendrite extension across a severed nerve section.
2. Description of Related Art
The peripheral and autonomic nervous system are formed by nerve cell bodies and processes, i.e., axons and dendrites forming bundles, innervating the skin, skeletal muscles, glands and related structures. The nerve cell bodies are situated in the brain, spinal cord or in ganglia. Each myelinated nerve fiber is enveloped by Schwann cells. In the case of unmyelinated fibers, several axons are enclosed in each Schwann cell. The Schwann cells are enveloped by a basement membrane, an extracellular matrix and an endoneurial mesenchymal sheath. Many such units form a nerve, which is limited by a perineurium of collagen, fibroblasts and related cells. An epineurium encloses the entire nerve, mostly comprising several nerve fascicles. A blood-nerve barrier prevents plasma proteins and many other substances from unrestricted penetration among the nerve fascicles. Motor and sensory nerves have the same structure but differ with regard to the axon and myelin dimensions. This means that in a mixed peripheral nerve it is not possible by the morphological characteristics to state whether a single axon is afferent or efferent. Autonomic nerve fibers, sympathetic and parasympathetic, are accompanying the sensory and motor nerve fibers as well as blood vessels.
Nerve cells and their supporting neurological cells are derived from the neuroectoderm. Although originally having a common embryonic origin, the nerve cells at an early state differentiate and obtain their structural characteristics. About four decades ago Hamburger and Levi-Montalcini demonstrated that the development of neurons are dependent on their target structures in order not to degenerate after differentiation. They provided direct evidence that neurons may die during normal development if not gaining synaptic contacts. This is true both for the central, peripheral and autonomic nervous systems.
The nerve cells in the central and peripheral nervous system reach their final number at about birth in mammals. The regenerative capacity present for peripheral and autonomic nerves during childhood is reduced with increasing age. This means that no new nerve cells are formed after birth, although axons and dendrites may regenerate to a limited extent. The autonomic system has a much higher regenerative capacity than the peripheral nervous system.
Injury to peripheral and autonomic nerves results in degeneration of the distal parts of the axons and dendrites. After dissection, Wallerian degeneration results in hypertrophy and hyperplasia of the Schwann cells lining the distal nerve. The proximal end of the injured axons retract to a variable extent, and, after a short lag period, the repair processes of the nerves begin.
Sprouts with finger-like extensions form a leading part of the outgrowing cell processes, the path of which is guided by the reactive Schwann cells. In most systems the rate of regeneration is in the range of 1-2 mm/day. Higher values have been documented for the autonomic nervous system. However, after about a month, depending on the test system examined, the rate of regeneration begins slowing down and eventually ceases. Little is known about the mechanisms which regulate the rate of regeneration. Detailed mechanisms of the regenerative process remain unknown.
Nerve crush is an injury of moderate severity, mostly resulting in complete recovery of the structure and function of injured axons and dendrites. It has been established that continuity of the basement membrane as well as early reestablishment of the microcirculation in peripheral nerves after crush injury is a prerequisite for complete recovery. Discontinuities in the basement membrane or even limited persistent blood vessel damage delay or impair the recovery.
Sectioning of a nerve results in discontinuity of the epi-, peri- and endoneuriums, as well as of the basement membrane enveloping the supporting Schwann cells with the enclosed axons and dendrites. Extensive vascular damage occurs as well. In the latter cases nerve regeneration starts after a delay of a few days in most clinical and experimental systems using peripheral nerves. Even meticulous microsurgery, almost reestablishing continuity of each nerve fascicle to each corresponding nerve fascicle by approximation, is not sufficient to gain any major improvement of the regeneration. Removal of the peri- and/or epineurium neither improves the extent of nerve regeneration, structurally or functionally. Most techniques used result in limited improvement as compared to if the nerve ends remained opposed. For example, further complications which occur in cases of sectioned peripheral nerves are the formation of neuroma and fibrous scar tissue starting after about a week. This eventually results in formation of neuroma and a permanent deficient function of the nerves. In the case of physical separation of peripheral nerves, the severed distal segment begins the process of Wallerian Degeneration soon after severing if microcirculation and reapproximation of the severed segment does not occur.
Adequate function of the target innervated by peripheral and autonomic nerves seems to be a prerequisite for maintenance of the function of the peripheral and autonomic neurons. Hamburger, et al. established that neurons depend on their targets for their survival. This means that damage to skeletal muscle cells, integumentum or glands result in disconnection of synapses from the target organ and more or less extensive degeneration of at least the distal parts of axons and dendrites. The degeneration may be of such extent that even neurons are lost. Recovery of the target organ may result in recovery of function after appropriate regeneration. Even in such cases, continuity of the fascicles, at least to the close vicinity of the target organs, and adequate microcirculation seems to be a prerequisite for successful regeneration.
As described in detail above, nerves are vital to the basic operation and function of the human body. Injury to a nerve can result in a partial or total loss of the sensation, control, or use of a member or portion of the body. Although methods currently exist for surgically repairing nerve tissue, such methods are not always possible and are commonly not completely successful in achieving a restoration of sensation, control, and use of the affected portion of the body.
One method for repairing served nerve involves the use of very fine sutures (multiple microsutures) to sew the severed nerve ends together. Such microsurgical procedures are typically conducted with the use of a microscope, which is tedious and time-consuming. Further, such microsurgical procedures are often not very successful, particularly in view of the large amount of time which typically transpires before surgery can be completed, as well as in view of the amount of manipulation which is required while the ends of the injured nerve are being meticulously sewn together using these microsurgical techniques. In addition, the improvement may be limited in spite of careful microsurgical reestablishment of connections between the nerve ends, presumably because reestablishment of close contact of severed nerve ends is not enough for successful nerve regeneration.
Where substantial nerve injury has occurred, it is often physically impossible to suture the severed nerve ends together. Thus, for more extreme nerve injuries, nerve grafts are often used as a nerve replacement. However, suture techniques and/or grafting have not always been sufficient for repair of a severe defect. Furthermore, suture under tension, gap reduction by stretching, mobilization, flexion of a joint, or rerouting may compromise sensitive intraneuronal vascularity, and autografts induce a second surgical site with requisite risks and complications. Moreover, in many instances, there was either no nerve growth or only growth of connective tissue. Thus, the functional results of surgical repair of peripheral nerve injuries have been disappointing in spite of improved surgical techniques.
Several techniques have been established since the pioneering work almost a century ago by J. Forssman, who demonstrated improved regeneration of peripheral nerves by using a reed as a guide. After that, several similar devices have been assigned, aimed to improve the nerve regeneration. Lundberg and Hansson (Brain Res 178, 573-576, 1979) developed a technique using a pseudomesothelial-lined chamber which obviously improved to some extent the nerve regeneration.
Conduits of various types have been investigated which consist of tubes of various composition (e.g. collagen, fascia, etc.) that are employed to act as a guide for nerve growth down a defined track in an attempt to promote anatomic reanastomosis by normal physiological procedures. Silicon tubes and tubes of biodegradable material have also been developed and extensively used.
These techniques seem to improve the initial outcome of the nerve regeneration, mostly due to a reduction in the extent of neuroma formation. In several reports significant although minor improvements could be demonstrated with regard to the number of nerve fibers reestablishing contact as well as increase in myelination and diameter of the axons. Unfortunately, a considerable proportion of the nerve fibers fail or cease to regenerate, and do not establish synaptic contacts. There is little to no difference between motor nerve fibers and sensory ones. This means that although structural contacts may be reestablished, deficiency in function persists. Furthermore, the greater length of time taken for the nerve regeneration results in atrophy and even extensive degeneration of target tissues such as skeletal muscles and skin structures, including glands and receptors. Thus, the longer the distance and the more extensive the damage, the benefits obtained using these technique for improving nerve regeneration have been minor.
Schwann cells in reactive nerves, injured by sectioning or by crush, exert positive influence in improved regeneration of peripheral nerve fibers. Crush of a nerve 2 weeks prior to a second injury results in improved regeneration as compared to non-primed nerves. Similarly, the use of a distal sciatic nerve as a target in conduit methods improves the regeneration of the sciatic nerve in rats. Predegeneration of the target nerve by injury one or 2 weeks prior to reestablishment of contact thus induces formation of factors seemingly improving long-term degeneration. Several different experimental systems have been established by various groups during the last decades (Sjoberg, J. and Kanje, M. (1990) Brain Res. 530:167-169). However, no specific factors have yet been identified or demonstrated to be responsible for the improved nerve regeneration.
The present invention provides a method and apparatus to stimulate regrowth of damaged nerves, in particular and to cause nerve fibers to extend and bridge a severed nerve section. The method for promoting regeneration of a damaged nerve comprises applying thermal energy to one or more nerve segments adjacent a damaged region of the nerve, such that nerve fibers from the treated segments are stimulated to grow and extend toward the damaged region. The damaged region of the nerve can be a terminus of a severed nerve or a region of a crushed nerve.
Various energy sources may be used to provide the thermal-mechanical stimulation of the nerve segment adjacent the damaged region, preferably thermal energy from thermal conductive or electromagnetic sources at low energy levels. Examples of thermal conductive energy sources include but not limited to resistive heating. Alternatively, the thermal energy may be generated by ultrasound. Examples of electromagnetic energy sources include but are not limited to radio frequency (RF) energy, coherent light, incoherent light, microwave and shortwave.
For example, thermal energy generated from a resistive heating source may be applied directly to opened segments of the damaged nerve. Alternatively, thermal energy may be applied superficially to treat the segments adjacent the damaged region of the nerve.
The one or more treated segments may be a nerve segment adjacent to the damaged region, preferably 1-18 mm, more preferably 2-15 mm, and most preferably 2-10 mm from the damaged region. Alternatively, the one or more treated segments may be a plurality of nerve segments located in region adjacent the damaged region, preferably in a region 5 mm to 20 mm distal to the damaged region.
The thermal energy applied to the segments of nerve adjacent the damaged region may be of a sufficient amount for heating the segments to a temperature in a range about 41-58xc2x0 C., preferably about 44-55xc2x0 C.
A guide template may be placed over the damaged region to direct nerve growth stimulated by the thermal energy. For example, the guide template may be a guiding filament (e.g., collagen, laminin or fascia) or a conduit (e.g., a wrapper, a cuff, or a tube) or a surgically prepared tunnel (e.g. laser, electrosurgical cautery, or auger mechanical tunnel). The conduit may be made of various materials derived from natural sources or synthetic materials. The conduit may be biodegradable or non-absorbable. Examples of conduit materials include but not limited to decalcified bone and vessels, fascia lata, fat, muscle, parchment, Cargile membrane, gelatin, agar, rubber, fibrin film, and various metals. The conduit is filled with nerve-growth-stimulating agents such as nerve growth factors.
An apparatus is provided for stimulating nerve growth, especially for regeneration of nerve injured by severance, crush and other physical forces. The apparatus comprises: an applicator including a proximal portion and a distal portion; and energy delivery mechanism that is coupled to the handpiece. The energy delivery mechanism may include an energy delivery surface that controllably delivers a sufficient amount of thermal energy to one or more nerve segments adjacent a damaged region of a nerve and stimulate nerve growth at the treated segments. Preferably, the energy delivery surface controllably delivers the thermal energy to and stimulates growth of one or more nerve segments adjacent the damaged region of the nerve. The amount of thermal energy may be sufficient for heating the segments to a temperature in a range of 41xc2x0 C. to 58xc2x0 C., preferably about 44xc2x0 C. to 55xc2x0 C. Optionally, the apparatus may include sensor coupled to the energy delivery mechanism, e.g. a temperature sensor for measuring temperature of the nerve segment.
The applicator of the apparatus may be configured to deliver a medium to the distal segment of the nerve, such as electrolyte solution, cooling fluid and medicaments. The applicator may also have a directionally biased distal end.
The energy delivery mechanism of the apparatus may include a variety of probes for delivering various type of energy to the nerve segment. Examples of such probes include but not limited to resistive heating electrodes, RF electrodes, Infrared probes, microwave probe, ultrasound emitters and optical fiber probes that are configured to be coupled to a coherent or incoherent light source configured to be coupled to an ultrasound generator.
The apparatus may optionally include a feedback control mechanism coupled to the energy delivery mechanism. The feedback control mechanism may comprises an energy control signal generator that generates an energy control signal to control energy supplied from an energy source to an energy delivery mechanism; and impedance measurement circuitry coupled to the energy delivery mechanism which measures impedance of a selected site. For example, the impedance measuring circuitry determines a minimum impedance value to determine a target impedance value as a function of the minimum impedance value, compares a measured impedance values to a target impedance value, and alters the control signal when said measured impedance value exceeds the target impedance value.
The apparatus with a feedback control mechanism may further include an energy source configured to supply energy to the energy delivery mechanism. Such an energy source is responsive to control signals directing the energy source to supply energy to the energy delivery mechanism.
The impedance measuring circuitry may includes such devices: a minimum impedance measuring device; a target determining device coupled to the impedance measuring device and configured to determine the target impedance value as a function of the minimum impedance value; and a comparison device for comparing measured impedance values to the target impedance value and generating a signal indicating whether the measured impedance value exceeds the target impedance value. Optionally, the impedance measurement circuitry may include a microprocessor controller.